1. Field of the Invention
The present invention relates generally to the field of cardiovascular physiology and atherosclerosis. More specifically, the present invention relates to the prevention and treatment of atherosclerosis by reducing the carbamylation of LDL or the effects of cLDL.
2. Description of the Related Art
Atherosclerosis is the main cause of many cardiovascular diseases in humans. Atherosclerosis is initiated by injury to cells of the vascular wall. One group of patients that is very susceptible to atherosclerosis is patients with renal insufficiency [1-3]. Patients with end-stage renal disease (ESRD) are at several-fold increased risk of developing cardiovascular pathology because of accelerated atherosclerosis. [1,2]. Even patients with mild renal insufficiency are at 2-3-fold higher risk of cardiovascular disease [3]. The high rate of cardiovascular complications cannot be entirely explained by the known cardiovascular risk factors in these patients.
There is a large body of data which indicates that an atherosclerotic lesion starts when the vascular endothelium is injured. The injured endothelium expresses adhesion molecules for the monocytes to bind to, and the monocytes burrow beneath the endothelial cell layer, ingest modified LDL, and form so-called “foam cells”. This process leads to the atherosclerotic plaque, which consists of a mass of lipid-engorged monocytes and macrophages covered by a fibrous cap being pushed out into the vessel lumen by proliferating smooth muscle cells [4-6].
When decrease renal function occurs, the increased amount of urea undergoes spontaneous (chemical, non-enzymatic) transformation to cyanate, which accumulates in patients with chronic renal failure (CRF). Cyanate acts as a potential toxin, inducing a modification of proteins called “carbamylation” [see reviews 7-9].
An example of the carbamylation reaction of free amino groups of protein N-termini is shown in FIG. 1. This reaction is 50 to 100 times faster with α-amino groups of amino acids than with ε-amino groups [7]. Isocyanic acid, the active form of cyanate, reacts irreversibly with nonprotonated groups of amino acids forming α-amino-carbamylamino acids from free amino acids. The irreversible carbamylation forming α-amino-carbamyl-lysine occurs in multiple lysine sites within a protein with accumulation over the life span of the protein. When a molecule of cyanate is removed by carbamylation, a new molecule of cyanate is formed because of the equilibrium between urea and cyanate. Reversible carbamylation occurs also at the hydroxyl groups of tyrosine, serine, or threonine, and the sulfhydryl groups of cysteine.
Very few studies have been aimed at the prevention of carbamylation, and all of them have involved lens protein [14, 15]. Incubation of rat lens in cyanate induces an aspirin-preventable increase in phase separation temperature [14]. Similarly, ibuprofen was found to induce a dose-dependent decrease in the binding of cyanate to lens protein [15]. It is possible that ibuprofen competes for cyanate binding sites. Aspirin was more effective when it was pre-incubated with lens protein, suggesting a predominantly covalent interaction. Bendazac also inhibits the carbamylation of lens protein when present with cyanate [16]. Therefore only aspirin, ibuprofen, and bendazac have been evaluated as inhibitors of carbamylation. There are no studies in which any amino acid has been used to prevent carbamylation of proteins or lipids.
The prior art is insufficient in the prevention and treatment of cardiovascular pathology caused accelerated atherosclerosis in normal individuals and deficient in the lack of an effective prevention and treatment of atherosclerosis in individuals with renal disease. The present invention fulfills this long-standing need and desire in the art.